Normal cardiac neural crest function is essential for normal structural and functional development of the heart and great arteries. We have shown that development of myocardial function is critically dependent on the earliest phase of cardiac neural crest development which occurs several days before the neural crest cells migrate into the outflow tract. While it is apparent that myocardial excitation-contraction coupling is depressed, we still do not understand the full extent of the functional deficit or its genesis. The alteration in myocardial function is not due to hemodynamic abnormalities present in the peripheral circulation or aortic arch arteries. Our collective data indicate that extracardiac signaling coordinated by the cardiac neural crest is required for normal myocardial maturation. The overall goal during the next funding period is to elucidate the molecular nature of myocardial dysfunction, establish the mechanism of signal coordination by neural crest cells, and determine factors that alter neural crest function. Project 1 will examine the modulation of an FGF-like signal originating form pharyngeal endoderm by neural crest cells, and the effect of excess retinoic acid on neural crest's ability to modulate this signal. Dr. Creazzo's project will establish the molecular and functional consequences of altered signal modulation in myocardial will establish the molecular and functional consequences of altered signal modulation in myocardial maturation. Dr. Lo's project will elucidate the cardiovascular consequences of Cx43 gap junction dysfunction in neural crest cells during migration into the pharyngeal region and outflow tract. The hypotheses to be tested by this application proposes a dramatic revision in the classical form-function hypothesis that has driven most earlier studies of cardiovascular development.